The Diagnostic Accuracy of Photopic Negative Responses Evoked by Broadband and Chromatic Stimuli in a Clinically Heterogeneous Population

Purpose: To compare the diagnostic accuracy of the photopic negative response (PhNR) elicited by red-blue (RB) and white-white (WW) stimuli, for detection of retinal ganglion cell (RGC) dysfunction in a heterogeneous clinical cohort. Methods: Adults referred for electrophysiological investigations were recruited consecutively for this single-centre, prospective, paired diagnostic accuracy study. PhNRs were recorded to red flashes (1.5 cd·s·m−2) on a blue background (10 cd·m−2) and to white flashes on a white background (the latter being the ISCEV standard LA 3 stimulus). PhNR results were compared with a reference test battery assessing RGC/optic nerve structure and function including optical coherence tomography (OCT) retinal nerve fibre layer thickness and mean RGC volume measurements, fundus photography, pattern electroretinography and visual evoked potentials. Primary outcome measures were differences in sensitivity and specificity of the two PhNR methods. Results: Two hundred and forty-three participants were initially enrolled, with 200 (median age 54; range 18–95; female 65%) meeting inclusion criteria. Sensitivity was 53% (95% confidence intervals [CI] 39% to 68%) and 62% (95% CI 48% to 76%), for WW and RB PhNRs, respectively. Specificity was 80% (95% CI 74% to 86%) and 78% (95% CI 72% to 85%), respectively. There was a statistically significant difference between sensitivities (p = 0.046) but not specificities (p = 0.08) of the two methods. Receiver operator characteristic (ROC) area under the curve (AUC) values were 0.73 for WW and 0.74 for RB PhNRs. Conclusion: PhNRs to red flashes on a blue background may be more sensitive than white-on-white stimuli, but there is no significant difference between specificities. This study highlights the value and potential convenience of using white-on-white stimuli, already used widely for routine ERG assessment

WFS1-Associated Optic Neuropathy : Genotype-Phenotype Correlations and Disease Progression

center dot OBJECTIVE: To evaluate the pattern of vision loss and genotype-phenotype correlations in WFS1-associated optic neuropathy (WON).center dot DESIGN: Multicenter cohort study. center dot METHODS: The study involved 37 patients with WON carrying pathogenic or candidate pathogenic WFS1 variants. Genetic and clinical data were retrieved from the medical records. Thirteen patients underwent additional comprehensive ophthalmologic assessment. Deep phenotyping involved visual electrophysiology and advanced psychophysical testing with a complementary metabolomic study. Main Outcome Measures: WFS1 variants, functional and structural optic nerve and retinal parameters, and metabolomic profile.center dot RESULTS: Twenty-two recessive and 5 dominant WFS1 variants were identified. Four variants were novel. All WFS1 variants caused loss of macular retinal ganglion cells (RGCs) as assessed by optical coherence tomography (OCT) and visual electrophysiology. Advanced psychophysical testing indicated involvement of the major RGC subpopulations. Modeling of vision loss showed an accelerated rate of deterioration with increasing age. Dominant WFS1 variants were associated with abnormal reflectivity of the outer plexiform layer (OPL) on OCT imaging. The dominant variants tended to cause less severe vision loss compared with recessive WFS1 variants, which resulted in more variable phenotypes ranging from isolated WON to severe multisystem disease depending on the WFS1 alleles. The metabolomic profile included markers seen in other neurodegenerative diseases and type 1 diabetes mellitus. center dot CONCLUSIONS: WFS1 variants result in heterogenous phenotypes influenced by the mode of inheritance and the disease-causing alleles. Biallelic WFS1 variants cause more variable, but generally more severe, vision and RGC loss compared with heterozygous variants. Abnormal cleftlike lamination of the OPL is a distinctive OCT feature that strongly points toward dominant WON. (Am J Ophthalmol 2022;241: 927. (c) 2022 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY license ( http://creativecommons.org/licenses/by/4.0/ ))Peer reviewe

Chiasmal Misrouting in Infantile Nystagmus Syndrome (INS): Phenotypes in Patients With Molecular Diagnoses

Chiasmal misrouting, once believed to be pathognomonic for albinism, has been reported in cases of INS, independent of melanin pathway disruption. The purpose of this study is to test the hypothesis that there are clinical-electrophysiological parameters that correlate with particular genotypes in INS

Cobalt-chromium toxicity and late-onset disease conversion in LHON - is there a causal link?

Lebers hereditary optic neuropathy (LHON, OMIM 535000) is the most common primary mitochondrial DNA disease in the population with the marked gender bias (male predominance) and the peak age of onset is in the second and third decades of life. However, presentation has been reported in patients from 2 to 87 years of age. There is increasing evidence that mitochondrial dysfunction can be influenced by environmental factors such as smoking, heavy drinking and particular drug agents. In addition, cobalt has been linked to mitochondrial dysfunction and ocular cobalt toxicity has been reported in the context of cobalt-chromium ions released from a metal hip prosthesis. The measurement of cobalt-chromium ions blood level is helpful in confirming the diagnosis, but there are challenges related to the laboratory methods used and the threshold level deemed to be toxic. We report a case, where cobalt-chromium ions leak possibly have contributed to disease conversion in late-onset LHON

The fovea regulates symmetrical development of the visual cortex

The foveal region contains the highest cell density in the human retina; consequently a disproportionately large area of the visual cortex is dedicated to its representation. In aniridia and albinism the fovea does not develop, and the corresponding cortical representation shows a reduction in gray matter volume. In albinos there are chiasmatic irregularities in the hemispheric projections, which are not found in aniridics. Here, we ask whether the anomalies in central retinal development, present in albinism and aniridia, have a wider impact on the architecture of the visual cortex. The length, depth, and topology of the calcarine fissure is analyzed in albino, aniridic, and normal subjects. These measures are compared between groups and between the cortical hemispheres within each subject. We show that the calcarine fissure, where the primary visual cortex is represented, is abnormally short in those lacking a fovea. Moreover, surface reconstructions of the calcarine fissure revealed marked interhemispheric asymmetries. The two groups could not be distinguished on the basis of their cortical features, and we therefore interpret the abnormalities in cortical architecture in terms of the absence of the fovea, the common retinal feature found in both groups

The diagnostic accuracy of photopic negative responses evoked by broadband and chromatic stimuli in a clinically heterogeneous population.

PURPOSE: To compare the diagnostic accuracy of the photopic negative response (PhNR) elicited by red-blue (RB) and white-white (WW) stimuli, for detection of retinal ganglion cell (RGC) dysfunction in a heterogeneous clinical cohort. METHODS: Adults referred for electrophysiological investigations were recruited consecutively for this single-centre, prospective, paired diagnostic accuracy study. PhNRs were recorded to red flashes (1.5 cd·s·m-2) on a blue background (10 cd·m-2) and to white flashes on a white background (the latter being the ISCEV standard LA 3 stimulus). PhNR results were compared with a reference test battery assessing RGC/optic nerve structure and function including optical coherence tomography (OCT) retinal nerve fibre layer thickness and mean RGC volume measurements, fundus photography, pattern electroretinography and visual evoked potentials. Primary outcome measures were differences in sensitivity and specificity of the two PhNR methods. RESULTS: Two hundred and forty-three participants were initially enrolled, with 200 (median age 54; range 18-95; female 65%) meeting inclusion criteria. Sensitivity was 53% (95% confidence intervals [CI] 39% to 68%) and 62% (95% CI 48% to 76%), for WW and RB PhNRs, respectively. Specificity was 80% (95% CI 74% to 86%) and 78% (95% CI 72% to 85%), respectively. There was a statistically significant difference between sensitivities (p = 0.046) but not specificities (p = 0.08) of the two methods. Receiver operator characteristic (ROC) area under the curve (AUC) values were 0.73 for WW and 0.74 for RB PhNRs. CONCLUSION: PhNRs to red flashes on a blue background may be more sensitive than white-on-white stimuli, but there is no significant difference between specificities. This study highlights the value and potential convenience of using white-on-white stimuli, already used widely for routine ERG assessment

Differential Changes in Color and Motion-Onset Visual Evoked Potentials from Both Eyes in Early-and Late-Onset Strabismic Amblyopia

PURPOSE. To examine changes in color-and motion-related visual function in patients with strabismic amblyopia. METHODS. Motion-onset and color visual-evoked potentials (VEPs) were recorded in 16 adult patients with strabismic amblyopia which had an early onset, before 18 months of age, and 14 patients with amblyopia of later onset. The results are compared with those from 21 normal adults. RESULTS. The peak times of motion-onset VEPs in the amblyopic eye were longer those than in the fellow eye in patients with both early-and late-onset strabismic amblyopia, but peak times in both amblyopic and fellow eyes were shorter than those in normal eyes. In patients with late-but not early-onset amblyopia, the peak times for color VEPs were significantly longer in amblyopic than in fellow and normal eyes. CONCLUSIONS. The patterns of abnormality for motion-onset and color VEPs in patients with strabismic amblyopia are different, probably indicating differential changes in function in magno-and parvocellular pathways. These abnormalities affect both the amblyopic and fellow eyes and are different in patients with an onset of amblyopia before or after 18 months of age. (Invest Ophthalmol Vis Sci. 2008;49:4418 -4426

Shifting mirrors: adaptive changes in retinal reflections to winter darkness in Arctic reindeer

Arctic reindeer experience extreme changes in environmental light from continuous summer daylight to continuous winter darkness. Here, we show that they may have a unique mechanism to cope with winter darkness by changing the wavelength reflection from their tapetum lucidum (TL). In summer, it is golden with most light reflected back directly through the retina, whereas in winter it is deep blue with less light reflected out of the eye. The blue reflection in winter is associated with significantly increased retinal sensitivity compared with summer animals. The wavelength of reflection depends on TL collagen spacing, with reduced spacing resulting in shorter wavelengths, which we confirmed in summer and winter animals. Winter animals have significantly increased intra-ocular pressure, probably produced by permanent pupil dilation blocking ocular drainage. This may explain the collagen compression. The resulting shift to a blue reflection may scatter light through photoreceptors rather than directly reflecting it, resulting in elevated retinal sensitivity via increased photon capture. This is, to our knowledge, the first description of a retinal structural adaptation to seasonal changes in environmental light. Increased sensitivity occurs at the cost of reduced acuity, but may be an important adaptation in reindeer to detect moving predators in the dark Arctic winter

Isolated rod dysfunction associated with a novel genotype of CNGB1

Purpose: To describe the clinical and electrophysiological features of an unusual retinopathy in a patient with a novel genotype of CNGB1, mutations in which are implicated in autosomal recessive retinitis pigmentosa (rod-cone dystrophy). Observations: A 61-year old asymptomatic woman was referred to the inherited retinal disorders clinic because of peripheral retinal pigmentary changes. She had normal visual acuity and color vision. Clinical examination and detailed imaging of the macula were normal, but there was atrophy of the outer retina in the periphery with sparse intra-retinal pigmentation. Electroretinography (ERG) revealed undetectable rod responses, with normal cone-mediated responses. The pattern ERG was normal. Genetic analysis identified two previously unreported variants in CNGB1: (c.2258T > A, p.[Leu753*] and c.807G > C, p.[Gln269His]), shown to be in trans. Conclusions and importance: This report describes a functionally cone-isolated retina in an adult, apparently hemizygous for a novel missense mutation in CNGB1, a novel phenotype for this gene. The p.[Gln269His] allele is the first missense change, within the glutamic acid-rich protein (GARP) domain of CNGB1, to be associated with retinal disease in humans. Keywords: Cone-isolated retina, Cyclic nucleotide-gated channels, Glutamic-acid rich protein (GARP), Night blindness, Retinitis pigmentosa, Rod dysfunctio